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Clinical and Translational Research

Efficacy, Outcomes, and Cost-Effectiveness of Desensitization Using IVIG and Rituximab

Vo, Ashley A.1,6; Petrozzino, Jeffrey2,3; Yeung, Kai1; Sinha, Aditi4; Kahwaji, Joseph1; Peng, Alice1; Villicana, Rafael1; Mackowiak, John5; Jordan, Stanley C.1

Author Information
doi: 10.1097/TP.0b013e3182802f88

Recent data (1, 2) indicate that Medicare expenditures for end-stage renal disease (ESRD) patients have increased dramatically with chronic dialysis representing the majority of costs ($30 billion per year) (1). Unfortunately, the increased expenditures have not resulted in improved outcomes (1, 2). In contrast, Medicare spends $2.4 billion per year for kidney transplantation, a therapy that offers lower mortality and improved quality of life (1–3). Because kidney transplantation represents a significantly better option for ESRD care, strategies to expand opportunities for transplantation are critical for cost containment and quality of life. Broadly sensitized ESRD patients (panel reactive antibody [PRA>80%]) account for less than 10% of deceased donor (DD) and less than 2% of living donor (LD) transplants (United Network for Organ Sharing [UNOS] 2000–2009) (3). Sensitized patients now represent an ever increasing number of transplant candidates because there are approximately 5000 failed allografts in the United States each year (4–6). Protocols for expanding DD and LD transplants among the broadly sensitized patients have resulted in an expansion of the number of transplants performed (7–13). However, debate over the effectiveness and cost/benefits of desensitization remain (14–16).

Our group has previously reported on the use of high-dose intravenous immunoglobulin (IVIG)+rituximab as desensitization agents (7–13).

Here, we examine the efficacy, cost-effectiveness, and outcomes of desensitization using high-dose IVIG (2 g/kg×2 doses)+rituximab (1 g) in a larger group of patients. Data are compared with a similar group of ESRD patients who were listed for transplantation on the UNOS wait list (2000–2010) (age [45–65 years] and cause of ESRD matched who are broadly human leukocyte antigen (HLA)–sensitized [PRA>80%]) and remained on dialysis or received transplants during this study period (17). In addition, an economic analysis of cost-effectiveness and outcomes of desensitization versus dialysis was performed (18, 19).

RESULTS

Efficacy of Desensitization

Two hundred seven (LD 56/DD 151) broadly sensitized patients (PRA>80%) were desensitized from July 2006 to December 2011. One hundred forty-six (45 LD/101 DD [71%]) patients (LD: 45/56 [80%]; DD: 101/151 [67%]) were successfully transplanted. The mean follow-up time was 30±17 months. The rate of transplantation per year for DD and LD recipients is shown in Figure 1A and B. Briefly, Figure 1A shows the rate of transplantation for DD recipients who received desensitization compared with HS (PRA>80%) patients awaiting transplantation on the UNOS wait list (17). The mean rate of transplantation was 67% over the 3-year period for desensitization compared with less than 10% for patients with PRA>80% on the UNOS wait list. Linear regression analysis shows a 5.5% increase in DD transplant rates per year compared with a 0.4% increase in HS patients remaining on the UNOS wait list. Rates of transplantation vary for the DD cohort based on donor-specific antibody (DSA) status, organ availability, and response to desensitization.

FIGURE 1
FIGURE 1:
A, rates of DD transplantation for patients on the UNOS wait list from 2005 to 2011 compared with the rates of transplantation of DD patients who received desensitization at our center. The average rate of transplantation was 67% per year with linear regression showing a 5.5% increase per year. This compares with a 10% transplantation rate for a comparable group of HS patients with 0.4% increase per year. B, rate of transplantation for HS LD recipients who were desensitized compared with a group of comparable patients awaiting LD transplantation from 2005 to 2011. The average rate of transplantation for those desensitized was 80% per year with linear regression showing a 7.2% increase in transplantation per year. This compares with a <2% transplantation rate for HS LD candidates who did not undergo desensitization with linear regression showing a 0.04% increase per year in transplantation rates. LD, living donor; DD, deceased donor; UNOS, United Network for Organ Sharing.

Figure 1B shows the rates of transplantation for HS LD recipients who received desensitization compared with HS patients awaiting LD transplantation without desensitization. The LD rate of transplantation in patients with PRA>80% is less than 2% per year for the nondesensitized group. However, 80% of desensitized LD patients with PRA>80% were transplanted over the 3-year observation period. Linear regression analysis indicate that desensitization is associated with a 7.2% increase in transplantation rate per year compared with 0.04% for HS patients awaiting LD transplants on the UNOS wait list.

Sixty-one patients (9 LD/52 DD [29%]) did not receive a transplant despite desensitization. Of these 61 patients, 44 (72%) had previous transplants as a sensitizing event and 59 remained alive and well on dialysis for the duration of the study. For this group, repeat desensitization with IVIG+rituximab±plasma exchange was done. Using this strategy, we transplanted 19 of the 59 patients who originally failed desensitization.

Clinical Outcomes of Transplantation After Desensitization

Twenty-nine percent of treated patients experienced acute rejections (22% C4d+ antibody-mediated rejection [ABMR] and 7% C4d- cell-mediated rejection); 5.5% of treated patients lost their grafts due to ABMR episodes. Graft loss occurred in 11 (8%) patients (death censored). There were eight immunologic losses and three nonimmunologic losses. Patient survival for LD and DD recipients is shown in Figure 2A and was 100%/95% up to 48 months after transplantation. Graft survival for LD and DD recipients was 95%/87.5% up to 48 months after transplantation, respectively (Fig. 2B). Mean serum creatinine values were acceptable (1.3 mg/dL) at 36 months in those with functioning grafts.

FIGURE 2
FIGURE 2:
A, patient survival for HS LD and DD recipients who received transplants after desensitization. Briefly, the patient survival is 100% and 95% at 48 months, respectively. B, graft survival (death censored) for HS LD and DD patients who received transplants after desensitization. Briefly, the graft survival is 95% and 87.5% at 48 months, respectively. LD, living donor; DD, deceased donor.

Figure 3 shows the cumulative probability of death in the matched ESRD cohort (17) that remained on dialysis during the observation period and were compared with 146 patients who were desensitized and transplanted. The death rate is approximately 21% at 3 years for those remaining on dialysis. This compares to a 3.4% mortality rate in the desensitized and transplanted patients.

FIGURE 3
FIGURE 3:
Probability of death after desensitization and transplantation in 146 patients (3.4% at 3 years) compared with a large cohort of patients (n=3754) who were wait listed for transplants, of similar age (45–65 years) and antibody characteristics (PRA>80%), and remained on dialysis during the observation period. The mortality shown is calculated based on UNOS reported data at 1 and 3 years of listing for transplantation. PRA, panel reactive antibody; UNOS, United Network for Organ Sharing.

Economic and Clinical Outcomes Analysis

Seventy-one percent of total patients were successfully desensitized with IVIG+rituximab at a cost of $28,090 followed by renal transplant (80% LD and 67% DD) at a cost of $92,799. Twenty-nine percent of sensitized patients were unresponsive to the desensitization regimen and were continued on dialysis at an annual cost of $84,639. Three-year costs for these nonresponders were included in the desensitization arm of the model according to an intention-to-treat analysis. For those patients undergoing transplantation, 22% developed ABMR at a cost of $25,000 during year 1 only. Nineteen percent of ABMR patients lost their grafts and returned to dialysis at a cost of $103,382 in year 1 followed by $84,639 annually for years 2 and 3. The other 81% of ABMR patients did not suffer graft loss and continued on immunosuppressants at $18,911 annually. Seventy-one percent of transplant patients did not experience ABMR and incurred only the $18,911 annually for immunosuppressants. In the comparator arm of the model, patients were assumed to remain on dialysis at an annual cost of $84,639.

Based on a 7% yearly mortality rate for dialysis patients, the estimated 3-year cost for patients treated in the desensitization arm of the model was $219,914 per patient compared with $238,667 per patient treated in the dialysis arm. Thus, each patient treated with desensitization and transplanted is estimated to save the U.S. healthcare system $18,753 (i.e., 7.9% of 3-year dialysis patient costs) 2011 USD in 3-year treatment costs on the average. Table 1 shows costs apportioned by time and outcomes over the 3-year observation period. The corresponding estimated 3-year savings, based on a 3.4% Cedars-Sinai mortality rate for desensitized patients remaining on dialysis, is $15,428 per desensitized and transplanted patient.

TABLE 1
TABLE 1:
Base case costs, apportioned by time and outcomes over the 3-year observation period, and based on 7% mortality rate for dialysis patients

Multivariate sensitivity analysis based on variation of costs for transplantation, ABMR, and year 1 graft loss each by ±20% demonstrated that desensitization remained dominant with 3-year savings of $435 to $33,747 per patient for all 104 cost scenarios modeled.

Based on a 7% yearly mortality rate for dialysis patients, overall estimated survival at the end of 3 years was 93.7% for patients in the desensitization arm of the model compared with 79.0% for patients in the dialysis only arm. Based on a 3.4% Cedars-Sinai mortality rate for desensitized patients remaining on dialysis, overall estimated 3-year survival was 96.6% for patients in the desensitization arm of the model compared with 79.0% for patients in the dialysis arm. Thus, the financial savings with desensitization are in addition to 14.7% to 17.6% greater probability of 3-year survival associated with desensitization versus dialysis only.

According to a 2009 nationwide estimate of inpatient healthcare utilization, there were 18,558 hospital discharges for kidney transplant procedures (International Classification of Diseases, Ninth Edition code 55.69, principal procedure only) (17). Based on this estimated annual number of U.S. transplant recipients, a 7% yearly mortality rate for dialysis patients, and assuming that 25% (i.e., 4640) would qualify for desensitization, the estimated aggregate annual savings in the United States would be 683 lives and $87 million (2011 USD) by using desensitization versus dialysis only. Of course, these estimates are affected by organ donor availability and allocation policies for sensitized patients.

Additional information on patient demographics and characteristics is shown in the supplemental digital content (see Table S1, SDC,http://links.lww.com/TP/A773).

DISCUSSION

Desensitization protocols emerged in the late 1990s as methodologies to deal with the increasing numbers of sensitized patients who waited years, often in futility, for an opportunity at successful kidney transplantation (8–13). These approaches using combinations of IVIG, plasma exchange, and rituximab have now gained acceptance. Archdeacon et al. (20) recently summarized the proceedings of a Food and Drug Administration symposium on desensitization and treatment of ABMR. An important concern is the absence of Food and Drug Administration–approved drugs for desensitization or treatment of ABMR. Despite these concerns, recent publications have summarized what is considered “best practices” for desensitization (9). Outcomes of desensitization have overall been good (7–12), but reports of protocol failures are also noted (14–16). The evolution of desensitization over the past decade has been inconsistent primarily because of the complexity of creating a nexus of therapy with antibody reduction and timing of transplantation to avoid ABMR.

With these issues in mind, we undertook a comprehensive assessment of the efficacy, outcomes, and cost-effectiveness of desensitization at our center. We compared outcomes to a similar group of age-matched and ESRD cause-matched patients with PRA>80% who remained on dialysis or received transplants during the study period. We felt this was critical because dialysis is the likely option for broadly sensitized patients (1). The mean wait time on dialysis for our sensitized patients was 114±56 months before desensitization. After desensitization, the mean wait time to transplantation was 4.4±4.9 months. We were able to transplant 146 of 207 patients treated. Most patients still remained crossmatch and DSA positive at the time of transplantation (7, 8, 11, 13). Thus, reduction in crossmatch and DSA levels is the goal of desensitization because total elimination of DSAs is rarely possible. With this approach, outcomes similar to those seen with nonsensitized patients at 3 years were obtained (Scientific Registry of Transplant Recipients [srtr.org] 2012) (21). Comparisons with the UNOS cohort are shown in Tables S2, S3, and S4 (see SDC,http://links.lww.com/TP/A773).

Recent data by Montgomery et al. (10) demonstrated a significant reduction in risk of mortality for HS sensitized patients who underwent desensitization and transplantation compared with patients who remained on dialysis or received dialysis or HLA-compatible transplant. Our analysis also is supportive of this conclusion when we analyzed sensitized patients who underwent transplantation without desensitization. The rates of transplantation for this group are approximately 10% per year with a 7% per year probability of death for the matched cohort of UNOS patients (17) (see Tables S2, S3, and S4, SDC,http://links.lww.com/TP/A773).

To our knowledge, the only randomized control trial of a desensitization therapy versus dialysis was conducted by our team (1997–2002) (22). This was a multicenter, placebo-controlled trial and showed efficacy of IVIG as a desensitization agent improving transplantation rates in the highly HLA sensitized patients (35% IVIG vs. 17% in placebo; P<0.05). Overall, the DD transplantation rates were 31% versus 12% (P=0.0137). This group was matched for all parameters mentioned above. Graft survival for the IVIG group was 80% and 75% for the placebo group at 30 months (P=NS). For the control group (17), we do not know the number of prior transplants and comorbidities, but we do know that the probability of death within 3 years of listing is approximately 21% for each cohort (2000–2006) and the transplantation rates for this group is 30% over the 3-year period with a 3-year graft survival of approximately 75%. Thus, the transplantation rates, death on dialysis, and transplantation outcomes for the UNOS listed patients has not changed for the past 10 years and is nearly identical to the data we obtained in our randomized control trial.

Adverse events were also assessed were minimal and similar to those previously reported by our group (23–26).

The costs of transplantation including all medications, organ acquisition, cost of treating rejection episodes, and cost of returning to dialysis for those with failed allografts were assessed and compared favorably with the costs of remaining on dialysis over the same period of time.

The most critical issue was the survival benefit engendered by transplantation in this cohort. At 3 years, the transplanted patients had a 14.7% to 17.6% greater probability of survival than those who remained on dialysis. Ultimately, this may be the strongest argument for broader implementation of desensitization.

MATERIALS AND METHODS

This study was approved by the Institutional Review Board of Cedars-Sinai Medical Center. Between July 2006 and December 2011, 207 broadly sensitized patients (DSA positive, PRA>80%) received desensitization with high-dose IVIG (2 g/kg×2 doses)+rituximab (1 g). All patients had flow cytometry PRA>80% and all had significant sensitizing events such as blood transfusions, pregnancies, and previous transplants. Those transplanted had an acceptable crossmatch at the time of transplantation (7, 8, 11, 13). Outcomes were compared with a group (n=3754) of broadly sensitized patients (PRA>80%, ages 45–65 years, and ESRD cause matched) who began dialysis in the year 2000 and were followed up to 5 years for assessment of probability of death while waiting for transplant (17). Parameters examined included efficacy of desensitization, patient and graft survival, survival rates on dialysis versus HS transplantation, acute rejection rate, and cost of desensitization versus cost of dialysis at 36 months.

Intravenous Immunoglobulin/Rituximab Desensitization Protocol

All HS patients received 10% IVIG (2 g/kg [maximum 140 g/dose] on days 1 and 30) and rituximab (1 g administered on day 15). Criteria for acceptance of DD and LD offers after desensitization and decision to proceed with transplantation as well as details of immunosuppression and posttransplantation management were previously described (7, 8, 11, 13). Campath-1H was used as the primary induction agent for HS patients (27).

An acceptable crossmatch is defined as a negative complement-dependent cytotoxicity at least at a 1:2 dilution of sera. Acceptable donor HLA-specific antibody levels include single antigen class I binding of less than 100,000 standardized fluorescence intensity/5000 mean fluorescence intensity and a positive donor flow cytometry T-cell crossmatch of less than 225 mean channel shifts. The acceptable B-cell crossmatch level is less than 250 mean channel shifts and single antigen bead binding of donor antigens less than 200,000 standardized fluorescence intensity/10,000 mean fluorescence intensity (11, 13). Solid-phase antibody analysis was also used to define the specificity of the antibodies detected (to follow the effect of desensitization) and the strength of DSA as reported previously (7, 8, 11, 13).

Cost Analysis of Desensitization and Transplantation Versus Dialysis

Cost were evaluated based on the U.S. Bureau of Labor Statistics consumer price index and were based on all urban consumers, not seasonally adjusted, U.S. city average for medical care. ESRD care and drug cost were based on data from Medicare and Medicaid (28, 29).

Dialysis Cost

The estimated annual cost of dialysis was based on a weighted average of 2008 Centers for Medicare & Medicaid Services spending for hemodialysis (95%) and peritoneal dialysis (5%) patients and inflated to $84,639 2011 USD assuming a 3.43% annual healthcare inflation rate (1, 18).

Cost of Desensitization

IVIG+rituximab desensitization costs of $27,166 (2010 USD) were estimated based on a regimen including two doses of IVIG (2 g/kg/dose) at a unit cost of $75.2 per gram, plus a single 1 g dose of rituximab at a unit cost of $6110 per gram, and assuming an average patient weight of 70 kg (28, 29). This cost inflates to $28,090 2011 USD based on an inflation rate of 3.4% for 2010 (18, 28).

Renal Transplantation Cost

Base case transplantation costs of $83,869 (2008 USD) were modeled based on Centers for Medicare & Medicaid Services reimbursement for transplant and organ acquisition (1). This cost inflates to $92,799 2011 USD based on a 3-year average inflation rate of 3.43% for 2008 to 2010 from the U.S. Bureau of Labor Statistics data (all urban consumers; not seasonally adjusted; U.S. city average for medical care) (28).

Immunosuppression Cost

Annual immunosuppression costs of $17,091 (2008 USD) were modeled based on Medicare reimbursement rates (1). This cost inflates to $18,911 2011 USD based on a 3-year average inflation rate of 3.43% for 2008 to 2010 (18).

Acute Rejection and Graft Loss Costs

Base case estimated acute antibody-mediated rejection costs of $25,000 included current (i.e., 2011) costs for ultrasound-guided kidney biopsy, 3 days of hospital stay, pulse steroids 10 mg/kg×3 doses, IVIG (2 g/kg), and rituximab (1 g). Costs are based on experience at Cedars-Sinai Medical Center.

Base case graft loss cost for year 1 after transplantation was estimated at $91,629 in 2008 USD (based on 2010 U.S. Renal Data System Reference Tables for Economic Costs of ESRD, Table K.13, Per person per year costs: patients with a graft failure within the year, all patients) and inflated to $103,382 2011 USD based on a 1991 to 2008 average inflation rate of 4.105% (1, 29, 30).

Three patients experienced graft loss without acute rejection during the 3-year follow-up period; one to cidofovir toxicity 5 months after transplantation without known hospitalization. For this patient, year 1 costs included desensitization, transplantation, 5 months of immunosuppression, and 7 months of dialysis. The second patient experienced technical loss. Year 1 costs included desensitization, transplantation, 4-day excess hospital stay following transplantation ($2144 per day based on average daily 2010 national hospital costs) (30), and a year of dialysis. Average year 1 costs for these two patients were used in the economic model. Years 2 and 3 costs for these two patients included dialysis only. The third graft loss was during year 3. Year 1 costs for this patient included desensitization, transplantation, and immunosuppression, year 2 costs included immunosuppression only, and year 3 costs included dialysis only.

Mortality

The observed probability of death at year 1 was 2.4% (1 of 42) for patients who were desensitized and transplanted with acute rejection and 3.8% (4 of 104) for patients without acute rejection. These deaths were modeled at the end of year 1 to include corresponding year 1 desensitization, transplantation, and acute rejection costs in the economic model. The annual probability of death was modeled at 7% for desensitized patients on dialysis and was applied at the end of years 1 and 2 (28–30). A separate analysis based on the Cedars-Sinai experience was done where the observed annual probability of death was 3.3% for desensitized patients remaining on dialysis.

Comparative Treatment Cost Model

A Markov model for treatment of ESRD patients was developed to compare the estimated treatment costs associated with desensitization followed by renal transplantation with the costs of dialysis (19). The decision tree analysis showing costs associated with each treatment pathway is shown in Figure 4. Cumulative costs were calculated during a 3-year time horizon. Accordingly, a 3% discount and 4.06% healthcare inflation rate were applied and compounded annually for years 2 and 3 (18). The 4.06% healthcare inflation rate was based on a 10-year average rate for 2001 to 2010 from the U.S. Bureau of Labor Statistics data (28). All costs are expressed in 2011 USD.

FIGURE 4
FIGURE 4:
Decision tree analysis of cost associated with remaining on dialysis compared with desensitization followed by transplantation. Cost is per patient per year and is attributed to outcomes.1Cost calculations as explained in the Patients and Methods section. 2Patients experiencing acute rejection and graft loss had no attribution of immunosuppression cost because all graft losses occurred within 3 months of transplantation. DWFG, death with functioning graft.

Statistical Analysis

Multivariate sensitivity analyses were performed by varying the following model inputs by ±20%: transplantation, acute rejection, and year 1 graft loss costs. Kaplan-Meier analysis was used to assess patient and graft survival.

ACKNOWLEDGMENTS

The authors thank the members of the Comprehensive Kidney Transplant Center and Transplant Immunotherapy Program and the dedicated members of the Transplant Immunology Laboratory and HLA Laboratory at Cedars-Sinai Medical Center who created an environment where these achievements are possible.

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    Keywords:

    Rituximab; IVIG; Broadly HLA sensitized; Desensitization; Dialysis cost; Economic cost model; Acute antibody-mediated rejection; Acute cell–mediated rejection; Kidney transplant outcomes; Markov model

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